Genome-Wide Screens in <i>Saccharomyces cerevisiae</i> Highlight a Role for Cardiolipin in Biogenesis of Mitochondrial Outer Membrane Multispan Proteins

Sauerwald, Julia; Jores, Tobias; Eisenberg-Bord, Michal; Chuartzman, Silvia; Schuldiner, Maya; Rapaport, Doron

doi:10.1128/mcb.00107-15

Cited by 31 publications

(26 citation statements)

References 36 publications

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“…In contrast, the non-bilayerforming phospholipids CL and PE are not required for the biogenesis of Tom22 (64,67). Moreover, the SAM-independent insertion of Tom20 occurs independently of CL, PE, and PC (64,67,68). Thus, PC is specifically required for the SAM-dependent protein import pathways.…”

Section: Discussionmentioning

confidence: 97%

Phosphatidylcholine Affects the Role of the Sorting and Assembly Machinery in the Biogenesis of Mitochondrial β-Barrel Proteins

Schuler

Bartolomeo

Böttinger

et al. 2015

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 97%

Phosphatidylcholine Affects the Role of the Sorting and Assembly Machinery in the Biogenesis of Mitochondrial β-Barrel Proteins

Schuler

Bartolomeo

Böttinger

et al. 2015

Journal of Biological Chemistry

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“…In mutants defective in CL or PE synthesis, the biogenesis of outer membrane ␤-barrel proteins is affected (49,50). Whereas CL is also required for the import of proteins with multiple ␣-helical membrane spans into the outer membrane, this import pathway remains largely unaffected in PE-deficient mitochondria (50,51). Furthermore, both phospholipids promote protein transport into the inner membrane and matrix (52)(53)(54)(55)(56)(57).…”

mentioning

confidence: 99%

Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria

Schuler¹,

Bartolomeo

Mårtensson

et al. 2016

Journal of Biological Chemistry

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Two protein translocases transport precursor proteins into or across the inner mitochondrial membrane. The presequence translocase (TIM23 complex) sorts precursor proteins with a cleavable presequence either into the matrix or into the inner membrane. The carrier translocase (TIM22 complex) inserts multispanning proteins into the inner membrane. Both protein import pathways depend on the presence of a membrane potential, which is generated by the activity of the respiratory chain. The non-bilayer-forming phospholipids cardiolipin and phosphatidylethanolamine are required for the activity of the respiratory chain and therefore to maintain the membrane potential for protein import. Depletion of cardiolipin further affects the stability of the TIM23 complex. The role of bilayer-forming phospholipids like phosphatidylcholine (PC) in protein transport into the inner membrane and the matrix is unknown. Here, we report that import of presequence-containing precursors and carrier proteins is impaired in PC-deficient mitochondria. Surprisingly, depletion of PC does not affect stability and activity of respiratory supercomplexes, and the membrane potential is maintained. Instead, the dynamic TIM23 complex is destabilized when the PC levels are reduced, whereas the TIM22 complex remains intact. Our analysis further revealed that initial precursor binding to the TIM23 complex is impaired in PC-deficient mitochondria. We conclude that reduced PC levels differentially affect the TIM22 and TIM23 complexes in mitochondrial protein transport.Mitochondria fulfill essential functions for the survival of the cell like energy conversion to produce ATP, synthesis of amino acids, lipids, and heme, as well as the generation of iron-sulfur clusters. They contain about 1000 proteins in yeast and 1500 proteins in humans (1, 2). More than 99% of the mitochondrial proteins are synthesized as precursors on cytosolic ribosomes. Mitochondria contain a sophisticated system of protein translocases to import precursor proteins (3-9). The translocase of the outer membrane (TOM 3 complex) forms the general entry gate for most precursor proteins. After passage of the TOM channel, distinct protein translocases sort the preproteins into the different subcompartments: the outer and inner membrane as well as the two aqueous compartments, the matrix and intermembrane space.The majority of mitochondrial proteins are sorted into the inner membrane and the matrix. Two inner membrane-bound protein complexes mediate protein import. The presequence translocase (also termed TIM23 complex) transports precursor proteins with a cleavable presequence into the inner membrane and the matrix, whereas the carrier translocase (also termed TIM22 complex) inserts proteins with multiple transmembrane segments into the inner membrane (3-9). The membrane potential across the inner membrane provides the driving force for both protein import pathways and is generated by the activity of the respiratory chain. Presequence-containing preproteins are directly transferred from the ...

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Section: Edited By Thomas Söllnermentioning

confidence: 99%

“…The exact role of the mitochondrial import complex and its mode of action is still unknown (23). Moreover, it has recently been shown that a few proteins may be able to insert into the OM independently of protein factors and that at least in one case this is facilitated by specific lipids (24,25).Mapping the variation of the import systems in different eukaryotes provides insight into the evolution of the mitochondrial protein import systems, which is key to understanding how the endosymbiotic ancestor of mitochondria converted into an organelle (26 -29 …”

mentioning

confidence: 99%

Biogenesis of a Mitochondrial Outer Membrane Protein in Trypanosoma brucei: TARGETING SIGNAL AND DEPENDENCE ON A UNIQUE BIOGENESIS FACTOR

Bruggisser

Käser

Mani

et al. 2017

Journal of Biological Chemistry

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Edited by Thomas SöllnerThe mitochondrial outer membrane (OM) contains single and multiple membrane-spanning proteins that need to contain signals that ensure correct targeting and insertion into the OM. The biogenesis of such proteins has so far essentially only been studied in yeast and related organisms. Here we show that POMP10, an OM protein of the early diverging protozoan Trypanosoma brucei, is signal-anchored. Transgenic cells expressing variants of POMP10 fused to GFP demonstrate that the N-terminal membrane-spanning domain flanked by a few positively charged or neutral residues is both necessary and sufficient for mitochondrial targeting. Carbonate extraction experiments indicate that although the presence of neutral instead of positively charged residues did not interfere with POMP10 localization, it weakened its interaction with the OM. Expression of GFP-tagged POMP10 in inducible RNAi cell lines shows that its mitochondrial localization depends on pATOM36 but does not require Sam50 or ATOM40, the trypanosomal analogue of the Tom40 import pore. pATOM36 is a kinetoplastid-specific OM protein that has previously been implicated in the assembly of OM proteins and in mitochondrial DNA inheritance. In summary, our results show that although the features of the targeting signal in signal-anchored proteins are widely conserved, the protein machinery that mediates their biogenesis is not.Mitochondria perform many important functions and are essential for all eukaryotes (1). Whereas a small number of proteins are synthesized in the organelle, Ͼ95% of the mitochondrial proteome is nuclear-encoded, synthesized in the cytosol, and subsequently imported into mitochondria (2-4). Mitochondria consist of four compartments: the outer and the inner membrane that surround the soluble intermembrane space (IMS) 2 and the matrix, respectively. Thus, nuclear-encoded proteins not only need to be targeted to mitochondria but also sorted to their correct intra-mitochondrial destination. The mitochondrial outer membrane (OM) is of special interest. It builds the interface between the organelle and the cytosol and forms a barrier across which all communication between the organelle and its surroundings must occur (5-7). Mitochondrial OM proteins mediate apoptosis, fission, fusion and interaction with other organelles as well as transport of metabolites and precursor proteins. Whereas mitochondrial protein import in general has been extensively studied, we still have large gaps in the understanding of the biogenesis of mitochondrial OM proteins (8 -11).Integral OM proteins are either anchored by a transmembrane ␤-barrel or by single or multiple ␣-helices. The single membrane-spanning proteins can be further categorized into N-terminal (signal)-anchored, internally anchored or C-terminal (tail)-anchored proteins. OM proteins generally contain internal targeting signals. For ␤-barrel proteins the OM targeting signal appears to be a dedicated ␤-hairpin motif (12), whereas for single membrane-spanning proteins the targeting signal...

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Genome-Wide Screens in Saccharomyces cerevisiae Highlight a Role for Cardiolipin in Biogenesis of Mitochondrial Outer Membrane Multispan Proteins

Cited by 31 publications

References 36 publications

Phosphatidylcholine Affects the Role of the Sorting and Assembly Machinery in the Biogenesis of Mitochondrial β-Barrel Proteins

Phosphatidylcholine Affects the Role of the Sorting and Assembly Machinery in the Biogenesis of Mitochondrial β-Barrel Proteins

Phosphatidylcholine Affects Inner Membrane Protein Translocases of Mitochondria

Biogenesis of a Mitochondrial Outer Membrane Protein in Trypanosoma brucei: TARGETING SIGNAL AND DEPENDENCE ON A UNIQUE BIOGENESIS FACTOR

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